Pulmonary Surfactant Protein-Hitchhiking Inhalable Vaccines Augment Mucosal and Systemic Antiviral Immunity

Mucosal immunity is vital to provide effective protection against respiratory virus infections. However, the effective delivery of vaccine antigen to the respiratory mucosa is challenging because of the natural mucosal barrier. Here, we describe an approach exploiting the natural pulmonary surfactant (PS)-associated protein as a chaperone for transportation across the pulmonary mucosal barrier to enhance the lung resident memory T (T_RM) cells, long-lived antibody response, and secretory immunoglobulin A (SIgA) generation via vaccination. Pulmonary immunization with an inhalable albumin-templated Mn nanoadjuvant (iMnNA)-formulated mucosal vaccine (MnVac) candidate promoted the <i>in situ</i>, local PS protein corona formation on iMnNA through binding to the albumin, thereby increasing the vaccine accumulation in pulmonary parenchyma and the antigen uptake by antigen-presenting cells (APCs). When formulated with a SARS-CoV-2 receptor-binding domain (RBD) dimer, this inhalable RBD-MnVac induced at least 3-fold higher and persistent (up to ∼240 days) RBD-specific antibody responses and higher frequencies in long-lived plasma cells (LLPC) in the bone marrow even at half antigen dose of the intramuscular immunization. The MnVac enhanced the systemic and local mucosal immune responses through activation of the stimulator of interferon genes (STING) pathway in the lung. Additionally, the heterosubtypic RBD dimer and influenza subunit MnVac extended the breadth of the protective antibody response against a number of viral variants. Overall, these findings support the use of iMnNA as a promising mucosal adjuvant candidate for fighting respiratory infectious diseases and future pandemics.